Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with anticancer treatment which can lead to early discontinuation of therapy and/or severely affect quality of life. Little is known about the mechanisms responsible for CIPN, and despite many CIPN therapeutic clinical trials, no standard evidence-based treatment exists. Excessive glutamate transmission has been implicated in the pathogenesis of peripheral neuropathy and neuropathic pain. Inhibition of the glial enzyme glutamate carboxypeptidase II (GCPII) has been shown to selectively dampen excessive glutamate transmission and alleviate neuropathic pain and protect peripheral nerves from the functional and histological deficits induced by chemotherapeutic agents. Based on these data, an orally bioavailable, thiol-based GCPII inhibitor was taken into clinical studies. Although the inhibitor was well-tolerated in Phase 1, subsequent immunological toxicities observed in GLP primate studies halted its development. Importantly the toxicity was not due to the GCPII mechanism, but rather due to the thiol moiety in the compound. As a class, thiol drugs have a risk of inducing hypersensitivity reactions. We now outline an iterative drug discovery plan to identify clinically viable non thiol GCPII inhibitors to test the hypothesis that this mechanism will provide therapeutic benefit to CIPN patients. Our iterative drug discovery plan includes a systematic zinc binding group replacement strategy, extensive in vitro drug-ability assessments, drug metabolism, in vivo pharmacokinetics, biomarker strategies, and evaluation of compounds in paclitaxel- and oxaliplatin-induced neuropathy and nerve crush efficacy experiments. Active compounds emerging from these efforts will be ready for IND enabling studies and ultimately clinical investigation in CIPN patients. PUBLIC HEALTH RELEVANCE: Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and common side effect of chemotherapy treatment rated by cancer survivors as one of the most disabling. Little is known about the mechanisms responsible for CIPN, and despite many CIPN therapeutic clinical trials, no standard evidence-based treatment exists. In several animal models, inhibitors of the glial enzyme glutamate carboxypeptidase II (GCPII) have been shown to protect peripheral nerves from chemotherapy-induced injury and prevent neuropathic pain symptoms, without affecting chemotherapy efficacy. We propose to synthesize potent, selective, orally available, and tissue penetrable GCPII inhibitors that when dosed concurrently with chemotherapy will attenuate CIPN severity. Drugs emerging from these efforts will be ready for IND enabling studies and ultimately clinical investigation in CIPN patients.